The candidate is an academic psychiatrist with a background in psychology, neuroscience, and behavioral genetics. He has a longstanding interest in schizophrenia. He has experience studying subclinical traits in family members of psychiatric patients as a method of trying to understand the nature of the inherited diathesis in mental illness. The hypothesis is that such "endophenotypes" are more highly penetrant in families, closer to the gene in the causal pathway, and will demonstrate simpler genetic architecture than the complex diseases to which they contribute. The current application proposes the initiation of a program of research on nailfold plexus visibility (NPV), a promising endophenotype for schizophrenia. NPV occurs at elevated rates in patients with schizophrenia, is specific to this disorder, and identifies a severe and highly familial subtype of schizophrenia. The trait itself is heritable and a strong positive correlation has been demonstrated between NPV and schizotypy scores in first degree relatives of high NPV patients. STUDY 1 of this proposal will attempt to replicate and extend recent findings that high NPV patients with schizophrenia also show greater deficits on frontal lobe tasks and more negative symptoms than other patients with schizophrenia, will examine the prevalence of the Deficit Syndrome in high NPV patients, and will assess brain structure variables and frontal white matter integrity in high NPV patients using structural and diffusion tensor magnetic resonance imaging. STUDY 2 will examine close relatives of high NPV patients and seeks to demonstrate that subtle forms of the clinical, neuropsychological and brain imaging findings seen in the high NPV patients also occur in their well family members, especially those with higher NPV levels. Subjects in STUDIES 1 and 2 will have blood drawn and DNA extracted and stored for future genetic studies. The results of this research will be used in designing linkage or association studies to locate the gene or genes involved in conferring the high NPV phenotype. The type of genetic endophenotype research proposed has the potential to increase sample homogeneity and greatly improve statistical power to locate susceptibility genes for schizophrenia. Furthermore, progress in understanding the genetic causes of schizophrenia should ultimately improve prevention, diagnosis and treatment of this common and devastating disorder. [unreadable] [unreadable] [unreadable]